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Enzyme-linked immunosorbent assays for quantification of MMAE-conjugated ADCs and total antibodies in cynomolgus monkey sera

文献类型：期刊论文

作者Pei, Min5,6; Liu, Tingting4; Ouyang, Lu4; Sun, Jianhua4; Deng, Xiaojie4; Sun, Xiaomin4; Wu, Wei4; Huang, Peng6; Chen, Yi-Li3; Tan, Xiaorong6
刊名JOURNAL OF PHARMACEUTICAL ANALYSIS
出版日期2022-08-01
卷号12期号:4页码:645-652
ISSN号2095-1779
关键词Monomethyl auristatin E Antibody-drug conjugates Pharmacokinetics Trophoblast cell surface antigen 2
DOI10.1016/j.jpha.2021.11.005
通讯作者Gong, Likun(lkgong@simm.ac.cn) ; Qin, Qiuping(qpqin@cdser.simm.ac.cn) ; Wang, Chunhe(wangc@simm.ac.cn)
英文摘要Antibody-drug conjugates (ADCs) are commonly heterogeneous and require extensive assessment of exposure-efficacy and exposure-safety relationships in preclinical and clinical studies. In this study, we report the generation of a monoclonal antibody against monomethyl auristatin E (MMAE) and the development, validation, and application of sensitive and high-throughput enzyme-linked immunosorbent assays (ELISA) to measure the concentrations of MMAE-conjugated ADCs and total antibodies (tAb, antibodies in ADC plus unconjugated antibodies) in cynomolgus monkey sera. These assays were successfully applied to in vitro plasma stability and pharmacokinetic (PK) studies of SMADC001, an MMAE-conjugated ADC against trophoblast cell surface antigen 2 (TROP-2). The plasma stability of SMADC001 was better than that of similar ADCs coupled with PEG4-Val-Cit, Lys (m-dPEG24)-Cit, and Val-Cit linkers. The developed ELISA methods for the calibration standards of ADC and tAb revealed a correlation between serum concentrations and the OD450 values, with R-2 at 1.000, and the dynamic range was 0.3-35.0 ng/mL and 0.2-22.0 ng/mL, respectively; the intra- and inter-assay accuracy bias% ranged from -12.2% to -5.2%, precision ranged from -12.4% to -1.4%, and the relative standard deviation (RSD) was less than 6.6% and 8.7%, respectively. The total error was less than 20.4%. The development and validation steps of these two assays met the acceptance criteria for all addressed validation parameters, which suggested that these can be applied to quantify MMAE-conjugated ADCs, as well as in PK studies. Furthermore, these assays can be easily adopted for development of other similar immunoassays. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of Xi'an Jiaotong University.
WOS关键词TROP2 EXPRESSION ; CHALLENGES ; STABILITY
资助项目China National Major Scientific and Technological Special Project for Significant New Drugs Innovation and Development[2019ZX09732002-006] ; National New Drug Creation Program of China[2018ZX09201017-004] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020223] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020330] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020360] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050305] ; National Natural Science Foundation of China[81872785] ; National Natural Science Foundation of China[81673347] ; Science and Technology Planning Projects of Department of Science and Technology Province[20190202] ; Shanghai Municipal Commission of Science and Technology of China[17431904400] ; Shanghai Municipal Commission of Science and Technology of China[19YF1457400] ; Shanghai Municipal Commission of Science and Technology of China[21S11904500] ; Major Scientific and Technological Special Project of Zhongshan City[191022172638719] ; Major Scientific and Technological Special Project of Zhongshan City[210205143867019]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER
WOS记录号WOS:000862894700013
源URL[http://119.78.100.183/handle/2S10ELR8/302670]  
专题中国科学院上海药物研究所
通讯作者Gong, Likun; Qin, Qiuping; Wang, Chunhe
作者单位1.Fudan Univ, Shanghai Engn Res Ctr Immunotherapeut, Sch Pharm, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
3.Dartsbio Pharmaceut Ltd, Res & Dev Ctr, Zhongshan 528400, Guangdong, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Biotherapeut Discovery Res Ctr, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Pei, Min,Liu, Tingting,Ouyang, Lu,et al. Enzyme-linked immunosorbent assays for quantification of MMAE-conjugated ADCs and total antibodies in cynomolgus monkey sera[J]. JOURNAL OF PHARMACEUTICAL ANALYSIS,2022,12(4):645-652.
APA Pei, Min.,Liu, Tingting.,Ouyang, Lu.,Sun, Jianhua.,Deng, Xiaojie.,...&Wang, Chunhe.(2022).Enzyme-linked immunosorbent assays for quantification of MMAE-conjugated ADCs and total antibodies in cynomolgus monkey sera.JOURNAL OF PHARMACEUTICAL ANALYSIS,12(4),645-652.
MLA Pei, Min,et al."Enzyme-linked immunosorbent assays for quantification of MMAE-conjugated ADCs and total antibodies in cynomolgus monkey sera".JOURNAL OF PHARMACEUTICAL ANALYSIS 12.4(2022):645-652.

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来源：上海药物研究所

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